Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population

Nora I Strom; Christie L Burton; Conrad Iyegbe; Talisa Silzer; Lilit Antonyan; René Pool; Mathieu Lemire; James J Crowley; Jouke-Jan Hottenga; Volen Z Ivanov; Henrik Larsson; Paul Lichtenstein; Patrik Magnusson; Christian Rück; Russell Schachar; Hei Man Wu; Danielle Cath; Jennifer Crosbie; David Mataix-Cols; Dorret I Boomsma; Manuel Mattheisen; Sandra M Meier; Dirk J A Smit; Paul D Arnold

doi:10.1038/s41380-024-02489-6

Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population

Mol Psychiatry. 2024 Mar 28. doi: 10.1038/s41380-024-02489-6. Online ahead of print.

Authors

Nora I Strom^{1

2

3

4}, Christie L Burton⁵, Conrad Iyegbe^{6

7}, Talisa Silzer⁵, Lilit Antonyan⁸, René Pool^{9

10}, Mathieu Lemire⁵, James J Crowley^{11

12}, Jouke-Jan Hottenga¹³, Volen Z Ivanov¹¹, Henrik Larsson^{14

15}, Paul Lichtenstein¹⁴, Patrik Magnusson¹⁴, Christian Rück¹¹, Russell Schachar⁵, Hei Man Wu⁷, Danielle Cath^{16

17}, Jennifer Crosbie⁵, David Mataix-Cols¹¹, Dorret I Boomsma^{10

13

18}, Manuel Mattheisen^{19

20

21}, Sandra M Meier^{20

21}, Dirk J A Smit^{22

23}, Paul D Arnold^{8

24}

Affiliations

¹ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany. nora.strom@hu-berlin.de.
² Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany. nora.strom@hu-berlin.de.
³ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Sweden. nora.strom@hu-berlin.de.
⁴ Department of Biomedicine, Aarhus University, Aarhus, Denmark. nora.strom@hu-berlin.de.
⁵ Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada.
⁶ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, England.
⁷ Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, USA.
⁸ The Mathison Centre for Mental Health Research & Education, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
⁹ Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
¹⁰ Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
¹¹ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Sweden.
¹² Departments of Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Netherlands Twin Register, Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
¹⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁵ School of Medical sciences, Örebro University, Örebro, Sweden.
¹⁶ Rijksuniversiteit Groningen and Department of Psychiatry, University Medical Center Groningen, Groningen, The Netherlands.
¹⁷ Department of Specialized Training, Drenthe Mental Health Care Institute, Assen, The Netherlands.
¹⁸ Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.
¹⁹ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
²⁰ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
²¹ Community Health & Epidemiology, Dalhousie University, NS, Halifax, Canada.
²² Amsterdam UMC location University of Amsterdam, Department of Psychiatry, Amsterdam, The Netherlands.
²³ Amsterdam Neuroscience, Compulsivity Impulsivity and Attention, Amsterdam, The Netherlands.
²⁴ Departments of Psychiatry and Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

PMID: 38548983
DOI: 10.1038/s41380-024-02489-6

Abstract

While 1-2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13-38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (P_fixed = 3.06 × 10^-5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (N_genes = 28, Beta = 0.79, SE = 0.16, P_bon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33-43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (r_G = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.

Abstract

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